Pyrrole perfluoroalkylation

Perfluoroalkylation can be accomplished via direct reaction of peifluoroalkyl halides and copper with aromatic substrates [232, 233, 234, 235, 236] Thus, perfluoroalkyl iodides or bromides react with functionalized benzenes m DMSO m the presence of copper bronze to give the corresponding perfluoroalkylated products directly in moderate to good yields [233] (equation 157) Mixtures of ortho, meta, and para isomers are obtained [232, 233], The use of acetic anhydride as solvent gives similar results [234, 235], Similarly, the direct reaction of perfluoroalkyl iodides and pyrroles with copper metal regiospecifically gives the 2-perfluoroalkylpyrroles [236] (equation 158). 

The N-pyrrolylzinc chloride 53 undergoes Pd-catalyzed coupling with perfluoroalkyl iodides to afford the 2-substituted pyrroles 54 in good yield [52], Smaller amounts (15-20%) of 2-perfluoroalkanoyl pyrroles, which presumably arise by hydrolysis of the benzylic difluoromethylene group, are also formed. This reaction, which is performed in one pot, also affords 2-phenylpyrrole (75%) and 3-phenylpyrrole (5%) with iodobenzene. Some biphenyl (15%) is also formed. 

Gly-OEt was also added to ethyl 3-perfluoroalkylpropynoates which were transformed in several steps into 5-perfluoroalkyl-substituted l-methyl-2-ethoxycarbonylpyrrolidin-3-ones (90X6705). 3-Propyl- and 4-propylpro-lines and 4- -pentylproline were synthesized from diethyl acetamidomalo-nate and an unsaturated aldehyde (67JA2459 72JMC1255). Ethyl benzyli-denecyanoacetate reacts with hippuric acid to give the pyrrole 8 (87H2323). 

The synthetic paths of fluorinated porphyrins (fluorine atoms or fluoroalkyl chains) are numerous and depend on the fluorination site (periphery or meso position). These syntheses are performed through the use of fluoroalkylated pyrroles, through DAST fluorination, or through direct perfluoroalkylation. Some examples are given next. 

The triazoline adducts from benzvalene (Scheme 21)162 and diphospha-benzvalene (Scheme 22) photolyze to yield novel tetracyclic aziridine ring systems165 that are valence isomers of azepines,162 whereas that from De-war thiophene (Scheme 20) gives a novel tricyclic aziridine that desulfurizes with triphenylphosphine to yield the trifluoromethylated Dewar pyrrole (Scheme 153).15 9,160 The stabilization of these strained molecules is attributed to the perfluoroalkyl effect.159... 

Pyrroles, furans, and thiophenes react preferentially with radicals at the 2-position. Thus, reaction of pyrrole with benzyl radicals gives 2-benzylpyrrole. In rather better yields, pyrrole and indole treated with per(poly)fluoroalkyl chlorides (RfCI) in the presence of sodium dithionite in DMSO produce 2-perfluoroalkyl products <2001JFC(111) 107>. Furans trap aryl radicals, generated from the Mn(OAc)3 oxidation of arylboronic acids <2003JOC578> or... 

Likewise, 2-perfluoroalkyl-substituted pyrroles were obtained on reaction of perfluoroalkyl iodides and pyrroles in the presence of stoichiometric amounts of copper (87MI3). Polytrifluoromethylation can be achieved by the same methodology with polyiodinated aryl and heteroaryl compounds (92T189) (Scheme 16). 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

This concept can also be applied for the synthesis of 3-perfluoroalkyl-and 3,4-bis(perfluoroalkyl)-substituted pyrroles [82JOC4779 91JFC(53)-285]. The Diels-Alder adduct from A-(tert-butoxycarbonyl)pyrrole and perfluoro-2-butyne exhibits remarkable thermal stability, but after a second [4 + 2] addition of 2,4,6-trimethylbenzonitrile oxide the newly formed adduct is capable of a retro-Diels-Alder reaction, giving 3,4-bis(trifluoro-methyDpyrroles (82S313). 

A variation of this method that removes the water produced in the pyrrole/aldehyde or hydrated aldehyde condensation has been used to produce meso-tetrakis(perfluoroalkyl)porphyrins. Lindsey s laboratory has also reported a rational synthesis of weyo-substituted porphyrins bearing one nitrogen heterocyclic group that can readily be used for preparing other mono-functionalized porphyrins, methods for minimi zing scrambling in the synthesisof tran -porphyrins from dipyrromethanes and aldehydes, and a rational synthesis of porphyrins bearing up to four different meso substituents. ... 

Trifluoromethylation of pyrrole (and indole and imidazole) occurs on irradiation of a mixture of the compound with difluorodiiodomethane, again via a SET mechanism involving fragmentation of the radical anion (Scheme 31). The presence of the CF3 group in the final products, 45 and 46, is a result either of secondary decomposition of the initially formed—but not isolated—difluoroiodomethyl derivatives, or of formation of the CF3 anion or radical in situ [94], Perfluoroalkyla-tion of pyrroles can also be achieved by an SrnI mechanism—by reaction with perfluoroalkyl iodides in the presence of magnesium or zinc [95]. Indole, on the other hand, gives a mixture of the seven possible alkylated derivatives when irradiated in the presence of ethyl chloroacetate [96],... 

The addition of S2CI2 or SCI2 to 2 equivalents of aminocinnamates or aminoacrylates 122 affords 2i/-l,4-thiazines 123, which—depending on R— extrude sulfur under the reaction conditions (R = Ar) or can be isolated and desulfurized by treatment with NEts to the corresponding pyrroles 124 (R = perfluoroalkyl) (84JOC4780 85JHC1621) (Scheme 34). 

After a brief survey of the history of valence-bond isomers of aromatic compounds, new syntheses and the reactions of these isomers reported in the last decade are reviewed. In the second chapter, the valence-bond isomers of homoaromatic compounds, especially benzene derivatives, are described and in the third chapter those of heterocyclic compounds. Photoreactions of perfluoroalkylated aromatic compounds afford valence-bond isomers in high yields. These isomers are very stable and useful for the synthesis of highly strained compounds. Therefore, the emphasis is put on the chemistry of trifluoromethylated benzvalenes, Dewar thiophenes, and Dewar pyrroles. 

D. The calculations confirm that the negative end of the dipole is towards phosphorus. - The calculated dipole moments of phosphole (1.9 D) and pyrrole (2.0 D) are similar, and, unlike furan, the positive ends of the dipoles are towards the heteroatoms. Dipole moments have been used, in combination with results from other methods of study, to estimate the preferred conformations of the dichloride (179), of the phosphites (180), and of triarylphosphine oxides. The use of dipole moments to aid stereochemical studies of compounds has been reviewed. Additive polarizability parameters should not be used in the calculations, and it has been recommended that data should be obtained from model compounds containing identical environments for the phosphorus atoms. The sensitivity of bond moments to structural changes has been studied perfluoroalkyl groups lower the phosphoryl bond moment, and the P—N bond moment is very sensitive to the valence state of the phosphorus atom. The conformational analyses of phospho-nates, phosphonamides, silyl phosphates, and a number of dioxaphosphori-nans (181) - have been reported. The P—Se bond moment has been estimated to be 1.24 D. The zwitterionic structure (182) was identified by its high dipole... 

Thermal reactions of iodo- or bromoperfluoroalkanes with heterocycles have led to perfluoroalkyl derivatives of pyridine230 232 (Eq. 71 )231 and pyrrole,233 while more recently it has been demonstrated that photochemical initiation is especially effective (Eq. 72).234... 

There are few examples of radical substitution of benzofnran or benzothiophene perfluoroalkylation of benzofuran is one snch, as illnstrated. This process can also be applied to 2-snbstitution of thiophene, pyrrole, imidazole and indole. 

Perfluoroalkylation. Arenes and heteroarenes give perfluoroalkyl derivatives upon reaction with RfS02CI under ruthenium complex catalysis. Pyrroles also undergo this reaction. ... 

Refluxing one equivalent of S2CI2 or SCI2 with two equivalents of the amino acrylates 133 in chlorobenzene gives pyrroles 137 in good yields, Scheme 34. Initial cyclization gives the 1,4-thiazines 135 from which sulfur is extruded via 136. This method is particularly useful for the preparation of perfluoroalkyl-substituted pyrroles, which are difficult to obtain by the Knorr synthesis (84JOC4780). 

Bouillon, J.P. Tinant, B. Nuzillard, J.M. Portella, C. Synthesis of new 3-(l-ethylsulfanyl-2-perfluoroalkyl)-5-hydroxy-5-methyl 5-phenyl)-l,5-dihydro-pyrrol-2-ones starting from y-keto thioesters and imines. Synthesis 2004, 711-721. 

Owing to their relatively low thermal stability, perfluoroacylperoxides [RpC(0)0]2 undergo thermal decomposition generating perfluoroalkyl radicals. Although [RpC(0)0]2 were successfully used for the perfluoroalkylation furane, thiophene, and pyrrole, the reaction of perfluoroacylperoxides with pyridine does not result in perfluoroalkylation, due to side reactions caused by interaction of the peroxides with a lone electron pair of nitrogen. Sterically hindered pyridines, however, were reported to give perfluoroalkylated products. For example, compound 1 reacts with peroxide 2 giving isomeric pyridines 3 and 4 in low yield (Fig. 7.1). ... 

Perfluoroalkyl radicals can be generated from perfluorosulfonyl chloride using RuCljCRPh,), as a catalyst. In the presence of 1-substituted pyrroles good yields of 2-perfluoroalkylpyrroles were obtained with N-substituents such as acetyl, benzenesulfonyl or trimethylsilyl. With tr/s-isopropylsilyl, however, 3-substitution was preferred. <94SC2049, 94JCS(P1)1339>... 

Perfluorinated heterocycHc compounds are of interest due to their synthetic uses and bioactivity. Bouillon and coworkers transformed fluori-nated fiirans into substituted pyrroles and 3-pyrrolin-2-ones (2004S711). 2-Perfluoroalkyl furans were treated with benzylamine in ether at room temperature for 16 h to provide a mixture of N-benzyl-3-pyrrohn-2-one diastereomers. 

---